The tricho-dento-osseous syndrome (TDO) is a highly penetrant autosomal dominant hereditary disorder that affects hair, teeth and bone. We have identified a four base pair deletion in the distal-less 3 (DLX3) homeobox gene as the molecular basis of this disorder and shown that all affected individuals in multiple kindreds have the same deletion. Despite affected individuals having the same four base pair deletion they show marked phenotypic variability in the hair, teeth and bone manifestations of TDO. Tooth size, bone thickness and bone density are highly variable in affected individuals. We hypothesize that this phenotypic variability of the major TDO features results from modifying genes or other genes of major effect. The special nature and size of the TDO population provides a unique opportunity to study the relationship between phenotype and genotype in people with the identical underlying molecular defect. We propose to identify modifying genes or other genes of major effect by the completion of three specific aims. Completion of specific aim 1 will provide increased numbers and detailed quantitative phenotype characterization of affected and unaffected members from families segregating for the same DLX3 deletion and ensure the power necessary to identify genetic phenotypic modifiers. Specific aim 2 is directed at identifying modifying genes or genes of major effect using two linkage analysis strategies. A candidate gene approach will be used to evaluate genes known to be important in or co-expressed with DLX3 in the tissues of interest. We have shown the feasibility of and will use a genome wide scan approach to search for additional important modifying gene loci. Information from the first two aims will be quantitatively evaluated to establish phenotype/genotype relationships in specific aim 3. Knowledge from these quantitative studies will be used to further focus both the phenotype and genotype studies of this population. Because of complexities in gene and environmental interactions it is typically difficult to correlate phenotype and genotype for what are considered simple Mendelian traits. This study provides a unique opportunity to advance our understanding of the relationship of phenotype and genotype and the genetic modulation of phenotype by taking advantage of a special human population, our current knowledge of the human genome and the power of current molecular biological approaches.